Tumoral RANKL activates astrocytes that promote glioma cell invasion through cytokine signaling

Kim, Jun Kyum; Jin, Xiong; Sohn, Young Woo; Jin, Xun; Jeon, Hyun Jeong; Kim, Eun Jung; Ham, Seok Won; Jeon, Hye Min; Chang, So Young; Oh, Seungmin; Yin, Jinlong; Kim, Sung Hak; Park, Jong Bae; Nakano, ﻿Ichiro; Kim, Hyunggee

doi:10.1016/j.canlet.2014.07.034

Cited by 67 publications

(58 citation statements)

References 23 publications

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“…Specifically, high endogenous expression of receptor activator of NF-κB (RANKL) in GBM cells leads to the activation of neighbouring astrocytes in the tumour microenvironment through NF-κB signalling. Activated astrocytes in turn signal back to the glioma cells to promote glioma invasion [66]. These findings are consistent with the demonstration that intercellular communication between neighbouring astrocytes and GBM cells, possibly mediated by secreted extracellular vesicles, plays key roles in GBM growth and invasion [67,68].…”

Section: Involvement Of Nf-κb In Glioblastoma Invasionsupporting

confidence: 80%

NF-κB Signalling in Glioblastoma

Soubannier

Stifani

2017

Biomedicines

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Nuclear factor-κB (NF-κB) is a transcription factor regulating a wide array of genes mediating numerous cellular processes such as proliferation, differentiation, motility and survival, to name a few. Aberrant activation of NF-κB is a frequent event in numerous cancers, including glioblastoma, the most common and lethal form of brain tumours of glial cell origin (collectively termed gliomas). Glioblastoma is characterized by high cellular heterogeneity, resistance to therapy and almost inevitable recurrence after surgery and treatment. NF-κB is aberrantly activated in response to a variety of stimuli in glioblastoma, where its activity has been implicated in processes ranging from maintenance of cancer stem-like cells, stimulation of cancer cell invasion, promotion of mesenchymal identity, and resistance to radiotherapy. This review examines the mechanisms of NF-κB activation in glioblastoma, the involvement of NF-κB in several mechanisms underlying glioblastoma propagation, and discusses some of the important questions of future research into the roles of NF-κB in glioblastoma.

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Section: Involvement Of Nf-κb In Glioblastoma Invasionsupporting

confidence: 80%

NF-κB Signalling in Glioblastoma

Soubannier

Stifani

2017

Biomedicines

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“…Nevertheless, even though this process initially aims to aid repairing the healthy brain tissue and fight the progression of the tumor, the same mechanisms might as well support tumor growth under the influence of GBM cells (O'Brien et al, ). Interestingly, the nuclear factor kappa‐B (Nf‐κB)‐dependent signaling might be involved in the activation of astrocytes into tumor‐associated astrocytes (TAAs) upon GBM growth (Kim et al, ). Indeed, receptor activator of Nf‐κB ligand (RANKL) has been reported to be produced by GBM cells, so it can reach its receptor RANK at the astrocytes' surface to activate them through the Nf‐κB pathway, leading to the rising of TAAs.…”

Section: Role Of Astrocytes During Glioblastoma Developmentmentioning

confidence: 99%

Astrocytes, the rising stars of the glioblastoma microenvironment

Brandao

Simon

Critchley

et al. 2018

Glia

141

117

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Glioblastoma (GBM) is an aggressive primary tumor, causing thousands of deaths worldwide every year. The mean survival of patients with GBM remains below 20 months despite current available therapies. GBM cells' interactions with their stromal counterparts are crucial for tumor development. Astrocytes are glial cells that comprise~50% of all brain cells and are therefore likely to establish direct contact with GBM cells. As other tumor cell types can hijack fibroblasts or immune cells to facilitate tumor growth, GBM cells can actually activate astrocytes, namely, the tumor associated astrocytes (TAAs), to promote GBM invasion in the healthy tissue. TAAs have thus been shown to be involved in GBM cells growth and limited response to radiation or chemotherapy (i.e., Temozolomide). Nevertheless, even though the interest in the cancer research community is increasing, the role of TAAs during GBM development is still overlooked.Yet, obtaining an in-depth understanding of the mechanisms by which TAAs influence GBM progression might lead to the development of new therapeutic strategies. This article therefore reports the different levels of GBM progression at which TAAs have been recently described to be involved in, including tumor cells' proliferation/invasion and resistance to therapies, especially through the activity of extracellular vesicles. K E Y W O R D S brain, glioblastoma, stromal cells, tumor associated astrocytes, tumor microenvironment

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“…Of note in this context is the capability of U87MG glioblastoma cells to induce astrocyte activation through the secretion of Receptor Activator of NF-kB ligand (RANKL), which in turn facilitates glioblastoma invasiveness in vivo by releasing FGF4, FGF6, TGF-β and Hepatocyte growth factor. [42] Consistently, co-cultured astrocytes display increased expression levels of a number of growth factors and cytokines and enhance invasiveness of glioblastoma stem-like cells. [43] Another decisive input could stem from astrocytes activated by the neoplastic lesion and the consequent up-regulation of matricellular proteins such as secreted protein acidic and rich in cys-teins (SPARC) in astrocytoma [44] and medulloblastoma [45] or connective tissue growth factor in glioma, [46] which jointly with additional matricellular proteins remodel neuronal tissue during development or after brain injury.…”

Section: Biophysical Properties Of the Brain Microenvironmentmentioning

confidence: 75%

“…[80] Despite of the fact that there is no blood flow and that the capillaries are not functional, it is likely that they are still capable of expressing and secreting various molecules, [81] which could affect other cell types in the slice culture including the tumor cells. In addition, the intriguing exchange between tumor cells and astrocytes and the suspected tumor promoting functions of astrocytes [41][42][43] urges for novel studies addressing the therapeutic potential of the astrocyte-tumor interaction, for which organotypic slice culture would be an ideal system. Along with their use for monitoring tumor dissemination, OBSCs have also been used for high resolution imaging of cytoskeletal structures in living glioblastoma cells.…”

Section: Organotypic Brain Slice Culture To Study the Micro Environmementioning

confidence: 99%

Dissecting brain tumor growth and metastasis in vitro and ex vivo

Grotzer¹,

Neve²,

Baumgärtner³

2016

JCMT

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Local infiltration and distal dissemination of tumor cells hamper efficacy of current treatments against central nervous system (CNS) tumors and greatly influence mortality and therapy-induced longterm morbidity in survivors. A number of in vitro and ex vivo assay systems have been established to better understand the infiltration and metastatic processes, to search for molecules that specifically block tumor cell infiltration and metastatic dissemination and to pre-clinically evaluate their efficaciousness. These systems allow analytical testing of tumor cell viability and motile and invasive capabilities in simplified and well-controlled environments. However, the urgent need for novel anti-metastatic therapies has provided an incentive for the further development of not only classical in vitro methods but also of novel, physiologically more relevant assay systems including organotypic brain slice culture. In this review, using publicly available peer-reviewed primary research and review articles, we provide an overview of a selection of in vitro and ex vivo techniques widely used to study growth and dissemination of primary metastatic brain tumors. Furthermore, we discuss how our steadily increasing knowledge of tumor biology and the tumor microenvironment could be integrated to improve current research methods for metastatic brain tumors. We believe that such rationally improved methods will ultimately increase our understanding of the biology of brain tumors and facilitate the development of more efficacious anti-metastatic treatments. Local infiltration and distal dissemination of tumor cells hamper efficacy of current treatments against central nervous system (CNS) tumors and greatly influence mortality and therapy-induced long-term morbidity in survivors. A number of in vitro and ex vivo assay systems have been established to better understand the infiltration and metastatic processes, to search for molecules that specifically block tumor cell infiltration and metastatic dissemination and to pre-clinically evaluate their efficaciousness. These systems allow analytical testing of tumor cell viability and motile and invasive capabilities in simplified and well-controlled environments. However, the urgent need for novel anti-metastatic therapies has provided an incentive for the further development of not only classical in vitro methods but also of novel, physiologically more relevant assay systems including organotypic brain slice culture. In this review, using publicly available peer-reviewed primary research and review articles, we provide an overview of a selection of in vitro and ex vivo techniques widely used to study growth and dissemination of primary metastatic brain tumors. Furthermore, we discuss how our steadily increasing knowledge of tumor biology and the tumor microenvironment could be integrated to improve current research methods for metastatic brain tumors. We believe that such rationally improved methods will ultimately increase our understanding of the biology of brain tumors ...

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Tumoral RANKL activates astrocytes that promote glioma cell invasion through cytokine signaling

Cited by 67 publications

References 23 publications

NF-κB Signalling in Glioblastoma

NF-κB Signalling in Glioblastoma

Astrocytes, the rising stars of the glioblastoma microenvironment

Dissecting brain tumor growth and metastasis in vitro and ex vivo

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